Tunable Gold‐catalyzed Reactions of Propargyl Alcohols and Aryl Nucleophiles

Abstract Gold‐catalyzed transformations of 1,3‐diarylpropargyl alcohols and various aryl nucleophiles were studied. Selective tunable synthetic methods were developed for 1,1,3‐triarylallenes, diaryl‐indenes and tetraaryl‐allyl target products by C3 nucleophilic substitution and subsequent intra‐ or intermolecular hydroarylation, respectively. The reactions were scoped with regards to gold(I)/(III) catalysts, solvent, temperature, and electronic and steric effects of both the diarylpropargyl alcohol and the aryl nucleophiles. High yields of triaryl‐allenes and diaryl‐indenes by gold(III) catalysis were observed. Depending on the choice of aryl nucleophile and control of reaction temperature, different product ratios have been obtained. Alternatively, tetraaryl‐allyl target products were formed by a sequential one‐pot tandem process from appropriate propargyl substrates and two different aryl nucleophiles. Corresponding halo‐arylation products (I and Br; up to 95 % 2‐halo‐diaryl‐indenes) were obtained in a one‐pot manner in the presence of the respective N‐halosuccinimides (NIS, NBS).

The combination of a C-1 alcohol leaving group in nonterminal propargyl alcohols 1 (Scheme 1b) and an external protic aromatic nucleophile ArH allows for a similar allene reaction pathway as the 1,3-acyl shift of propargyl esters (Scheme 1a-ii). Thus diaromatic (Ph I , Ph II ) propargyl alcohols 1 and aryl nucleophiles are reported to give triaryl-allenes 3 and indenes 4 by gold catalysis (Scheme 1b). [27] The initial allenes 3, formed by i) S N 2' nucleophilic aryl attack at C3, undergo subsequent ii) intramolecular hydroarylation by a Nazarov cyclisation-like step [28,29] by heating, to give indene product 4 (Scheme 1c). Whether heating assisted the Au-allene interaction or the Nazarov cyclisation was not discussed. In general, the indene formation by ii) cyclisation (Scheme 1c) of the vinyl-gold intermediate could potentially take place by incorporation of either of the two phenyl groups (Ph I or Ph II in Scheme 1) of allene 3. Reaction with Ph I would proceed via a doubly stabilized benzylic carbocation but would give a potential geminal di-aryl-substituted indene product. However, as proved by the obtained indene products 4, steric effects and incorporation of Ph II via the planar gold cationic mono-benzylic intermediate, seemed to be dominant for successful reactions. An alternative iii) intermolecular hydroarylation pathway of allenes 3 with a second aromatic nucleophile Ar'H, affording 1,1,3,3-tetraaryl-allylic product 5, could be envisioned, but has not previously been studied. [30] Additionally, the competing direct iv) aryl C1 nucleophilic substitution on propargyl alcohols 1 would yield 1,1,3-triarylpropargyl products (2) by gold catalysis, [30][31][32] also known with other transition metals or Lewis acids. [33][34][35][36] Allenes are important subunits in a variety of natural products and pharmaceutically related compounds, [37] as well as versatile synthons in synthetic organic chemistry because of their ability to undergo a diversity of transformations in interor intramolecular fashion. Gold interacts with allenes, and may form stable, isolable complexes. [38] Gold-catalyzed transformations of allenes mainly involve cycloadditions or inter-/intramolecular nucleophilic addition reactions, [39] including hydroarylations. [40] Thus, a variety of carbo-or heterocycles can be produced by allene cyclizations. [41] The gold catalyst can coordinate to either allenic double bond, and the regioselectivity of the subsequent nucleophilic attack depends on the structure of both the allene substrate and the reactant, and different products may be formed. Hence, efficient and simple approaches for allene synthesis are important. In addition to the presently studied synthesis of allenes by gold-catalyzed intermolecular reaction of benzylic propargylic alcohols and aryl nucleophiles, [42] allenes are normally synthesized by prototropic rearrangement of the corresponding propyne, [43,44] by sigmatropic rearrangements, [45,46] as well as Cu II -catalyzed coupling, additions to enynes, 1,2-eliminations and Wittig-type reactions. [47,48] The indene (1H-indene) structure moiety (4) is an attractive scaffold due to its biological activities. [49,50] Indene is a stable structure, resisting oxidation of the cyclopentene ring even by harsh conditions. [51] Several metal-catalyzed reactions [2,[52][53][54][55] are used for synthesis of substituted indenes. The Au-catalyzed indene cyclisation of propargyl acetates proceeds through the allene precursor and gives different indene regioisomers [1,56] by 1,2-and 1,3-acyl shift, followed by hydroarylation. [56] This reaction is further developed with propargyl alcohols. [30] The Fiksdahl research group is currently working on the development of novel Au I and Au III complexes. We have established a set of standardized Au-catalyzed test-reactions for screening and evaluation of the catalytic ability of new Au I and Au III complexes. The results demonstrate how the catalyst properties and stability are dependent on ligand structure, and the importance of ligand design. High catalytic activity has been proved in selected test reactions, such as propargyl based transformations. [10][11][12][13][14][15][16]21,[23][24][25] As gold-catalyzed transformations of nonterminal propargyl alcohols are not commonly reported, we wanted to investigate the potential of the reaction of propargyl alcohols 1 with aromatic nucleophile ArH (Scheme 1) in order to be included in our list of gold-catalyzed model reactions. Based on the previous studies [30] of the reaction, which applied a limited choice of Au catalysts and mainly focused on formation of the indene product 4, we have carried out a more comprehensive study to look closer at reaction conditions and additional products. With the aim of understanding factors favoring selective synthesis of allenes 2, indenes 4 and possible tetraaryl-allylic 5 products, the reactions were scoped with regards to solvent, Au catalyst, electronic and steric effects of propargyl alcohol 1 and aryl nucleophiles.

Synthesis of Propargyl Alcohols
A range of propargyl alcohols 1a-i with varied electronic and steric properties were prepared from electron-rich and electrondeficient aldehydes 6a-e and arylalkynes 7a-d (Scheme 2).

Au-Catalyzed Reactions of Propargyl Alcohols with Aryl Nucleophiles
It soon became clear that the reactions of propargyl alcohols 1 with aryl nucleophiles ArH (Scheme 1b,c) were more complex than previously reported. In addition to variable ratios of allene 3 and indene 4 products, also the competing C1 substitution products 2 and 2 solv could be formed, depending on the nucleophilic ability of ArH and solvent. Our hypothesis was that the reaction of propargyl alcohols 1 and aryl nucleophiles could be tuned to give either the initially formed allene 3 by C3 substitution or to further proceed to the 1,3-diaryl-indene product 4 by intramolecular hydroarylation. Consequently, the scope of the reaction and the allene 3 /indene 4 product selectivity was investigated by varying time, temperature, gold catalyst, solvent (Table 1), propargyl alcohol ( Table 2) and aryl nucleophile (Table 3a). Also, the formation of tetraaryl-allyl products 5 was studied by intermolecular hydroarylation of allene 3 with a second nucleophilic aryl compound (Table 4). 1 H NMR product quantification of reaction mixtures readily gave essential information of the outcome of the reactions. The relative abundance of formed compounds was determined by integration of selected characteristic 1 H NMR signals (Table 1) in the spectrum of crude product mixtures. New products 1-5 were also synthesized, isolated (% yields, Tables 2, 3) and characterized ( 1 H and 13 C NMR, HRMS). Full 1 H, and 13 C NMR data assignments of products 2-4 (based on 2D NMR studies; COSY, HSQC, HMBC, NOESY), are available in the Supporting Information.

Effect of Time, Temperature, Solvent and Gold Catalyst
Initial studies verified that proper choice of reaction time and temperature could favor formation of either allene 3 or indene Scheme 2. Synthesis of propargyl alcohols 1a-i. [a] Standard procedure: A mixture of Au catalyst (5 mol %), propargyl alcohol 1a (1 equiv. and MesH (6 equiv.) in solvent (1 mL) was stirred at given temperature and time before addition of water, a few drops of NEt 3 and extraction into diethyl ether, followed by removal of solvent in vacuo. 4 target products. Hence, the reactions of substrate 1a with mesitylene nucleophile (MesH, 6 equiv.) in trifluoroethanol (F 3 -EtOH) were tuned both for selective formation of allene 3a (r.t., 15 min) and the diaryl-indene 4a, (80°C, 1.5 h). A selection of commercially available Au I and Au III catalysts (5 mol %) were tested (Table 1). It appeared that the choice of gold salts strongly affected the outcome of the reactions. The two tested Au I salts JohnPhosAu(ACN)SbF 6 and Me 2 SAuCl (entries 1,2), were weak catalysts for the initial allene 3a formation (19 % at r.t., 15 min), and large amount of substrate 1a (74 %) remained unreacted. In contrast, Au III salts (AuCl 3 , AuBr 3 , KAuCl 4 ) generated the initial allene 3a product in high yields (85-91 %; entries 3-5) by similar mild conditions. However, both Au I and Au III salts afforded high conversion into indene product 4a by heating (90-95 %; 80°C, 1.5 h; entries 1-5). KAuCl 4 generated the initial allene 3a most selectively (91 %); while Me 2 SAuCl afforded the final indene product 4a most efficiently (95 %) by heating. But only gold(III) salts were unique to allow appropriate temperature tuning of the reactivity to give high yields of both allene 3a or indene 4a target products in F 3 -EtOH.
Previously reported studies concluded that the AuBr 3catalyzed formation of indene 4 was strongly dependent on the solvent, as the reaction was unsuccessful in refluxing toluene and THF, while moderate to high yields were obtained in DCE and CF 3 -EtOH at reflux. [30] To avoid fluorinated solvents, other more conventional solvents for gold catalysis were attempted for indene formation (Table 1, entries 6-10). Competing nucleophilic C1 substitution by the aryl nucleophile MesH or the solvent (F 3 -EtOH) was expected to take place to give varying amounts of unwanted by-products 2a and 2a solvent . In ethanol, the propargyl ether 2a OEt was mainly formed (76 %, entry 6), while in acetonitrile (entry 7), the C1 aryl substitution product 2a dominated (2a: 4a; 3 : 1 ratio). As not all gold complexes may be compatible with F 3 -EtOH, nitromethane could serve as an alternative non-fluorinated solvent for the reaction. High reactivity and selectivity were obtained in MeNO 2 (85 % indene 4, entry 8), but somewhat lower than in F 3 -EtOH (93 %, entry 4). Reduced reactivity would be expected in DCM, a common solvent for Au catalysis, due to lower reflux temperature. In fact, only modest conversion of substrate 1a into allene 3a (57 %) and indene 4a (5 %) took place in DCM (entry 9).
Standard activation of Au I -Cl pre-catalysts by anion exchange with an appropriate weakly coordinating anion is performed by addition of 1 equiv. of the respective silver salt. However, increased yields in gold(III)-catalyzed reactions, including AuCl 3 and Au III -NHC, have been obtained by increasing the number of equivalents of AgSbF 6 (from 1 to 2), presumably due to generation of a more electrophilic gold(III) species. [57][58][59] In fact, a dramatic effect of the AuBr 3 -catalyzed reaction in DCM was observed by addition of AgSbF 6 (2 equiv.), and full conversion of substrate 1a gave highly selective formation of allene 3a (90 %, r.t., 15 min) and indene 4a (94 %, reflux (40°C), 5 h), respectively (entry 10).
Thus, highly selective formation of either allene 3a or indene 4a from propargyl alcohol 1a may take place at low and high temperature, respectively. By varying reaction time and temperature, as well as gold catalysts and solvents, the most promising tunable catalytic conditions were obtained by the Au III halide salts (AuCl 3, AuBr 3, KAuCl 4 ) in F 3 -EtOH, or with gold(III) catalysts AuBr 3 -(AgSbF 6 ) 2 and Au III Cl 3 -SIPr-(AgSbF 6 ) 2 in DCM. The scope of the reaction was therefore further studied.
Thus, successful tunable formation of target allene 3 or indene 4 products seems to require moderately activated Ar 3 H alkylbenzene nucleophiles, while strong alkoxyaryl nucleophiles react by undesired C1 substitution. The pure allene 3j (99 %)   and indenes 4j and 4k (unstable; 56 % and 15 %) were prepared for characterization (NMR, HRMS). The developed haloarylation strategy to synthesize functionalized 2-haloindenyl from propargylic alcohol substrates represents a gold-catalyzed tandem reaction with aryl carbon nucleophiles, in contrast to other similar iodination reactions, which include heteroatom nucleophiles. [61][62][63][64] The 2-halo-sp 2carbon moiety represents a versatile reactive position for subsequent transformations, such as a series of efficient Pd-catalyzed CÀ C coupling reactions, which may give rise to a great variety of indene based target products.

Tetraaryl-allyl Products 5:
Attempts with allene 3a to follow an alternative competing gold(III)-catalyzed intermolecular hydroarylation pathway with a second external aryl nucleophile (Ar 4 H) to afford 1,1,3,3-tetraaryl-allyl products 5 were promising ( Table 4, Scheme 3c). By a one-pot procedure, addition of the heterocyclic indole to the initially formed allene 3a reaction mixture, efficient incorporation of 3-indole took place by intermolecular hydroarylation. The amount of target tetraarylallyl product 5a increased by heating from 1.5 h to 6 h (27-81 %; 80°C, entries 1,2). The preferred site for electrophilic substitution on indole is C3 rather than C2, as expected from the greater electron density at C3 of the enamine structure moiety and higher stabilization of the iminium cation formed by C3 attack. In contrast to most aryl nucleophiles Ar 4 H below (entries 6-10), the indole reactions afforded target 3-indolsubstituted product 5a as E/Z double-bond stereoisomers (6 : 1). The facts that no conversion took place at r.t., and that the competing indene by-product 4a was only formed in minor amounts (5 %), may indicate that the gold(III)-catalyzed indole hydroarylation follows a different reaction mechanism than the other aryl nucleophiles.
Our results for intermolecular hydroarylation with fivemembered heterocycles were in accordance with expected reactivity and positional selectivity. The order of reactivity in electrophilic substitution of these heterocycles has been shown to be thiophene < furan ! pyrrole. [65] In contrast, it is known that the C3-/C2-positional selectivity (β : α ratio) of fivemembered heterocycles increases with increasing ability of the heteroatoms to stabilize the corresponding onium states of the elements (O + < S + < N +). [65] The less reactive thiophene did undergo a more efficient hydroarylation with a large excess of thiophene (5 equiv., entries 3-4), also without heating. The thiophene nucleophile gave regioselective 2(α)-substitution products 5b (obtained as a 5 : 1 mixture of E/Z isomers) as sulfur provides insufficient stabilization relative to the indole cation giving 3-substitution. Thiophene did additionally undergo double hydroarylation to give mixtures of 2-mono-and 2,5-bisproducts 5b and 5b-bis (32 %; 28 %; entry 4). However, almost selective formation of the bis-product 5b-bis (43 %) was observed with a limited amount of thiophene (0.5 equiv., entry 5), demonstrating the higher nucleophilic ability of the mono-product 5b to undergo a second hydroarylation. We attempted to identify the double-bond stereoselectivity of the indole and thiophene product 5a and 5b product mixtures by NOESY NMR but no conclusive data were obtained. However, based on steric factors of the bulky tetraaryl-allyl structure, the E-double bond would be expected in all products 5, as shown in Scheme 3. The furan nucleophile also demonstrated the expected preference for α-substitution. Being more electron-rich and reactive, furan favored complete bis-hydroarylation and gave the 2,5-bisfuran product 5c-bis (45 %, 80°C, 1.5 h, entry 6) from equimolar reactions, while benzofuran afforded mono-hydroarylation product 5d by C2 attack (69 %, r.t., 24 h, entry 7). Electrophilic substitution of benzothiophene usually give both α and β isomers. Thus, the benzothiophene reactions gave 1 : 1 mixtures of C2-/C3-regioisomers 5e 2 and 5e 3 (48 % in total, entry 8). Benzothiophene was less reactive towards the electrophile than thiophene (60 %, entry 4). Both the slightly and the highly activated phenyl derivatives, anisole and 1,3,5-triOMebenzene, successfully afforded the respective tetraaryl-allyl products 5f,g in variable degrees by similar conditions (45-73 %, r.t., 24 h, entries 9, 10). Selective para attack afforded anisole-product 5f.
At higher temperature, benzofuran, benzothiophene, anisole and 1,3,5-tri-OMe-benzene were not incorporated by intermolecular hydroarylation, as the competing indene 4a (90-95 %) formation took place by selective intramolecular hydroarylation (entry 11). By similar harsh conditions, the reactive furan, pyrrole and N-Me-pyrrole Ar 4 H nucleophiles only gave undefined product mixtures via allene 3a (entries 12, 13). By addition of aniline or hydrazine-Boc nucleophiles to the allene 3a reaction mixture at r.t., no further reaction took place and allene 3a was recovered, probably due to amine N-coordination and deactivation of the gold catalyst, demonstrating that gold catalysis is required for subsequent indene 4a formation.

Experimental Section General
All reactions, except the synthesis of gold complexes, were performed under inert N 2 -atmosphere. Commercial grade reagents were used without any additional purification. Dry solvents were collected from a MB SPS-800 solvent purification system. All reactions were monitored by NMR and/or thin-layer chromatography (TLC) using silica gel 60 F254 (0.25 mm thickness). TLC plates were developed using UV-light, p-anisaldehyde stain, or I 2 stain. Flash chromatography was performed with Merck silica gel 60 (0.040-0.063 mm). 1 H and 13 C NMR spectra were recorded by a Bruker Avance DPX 400 MHz or a Bruker Avance III 600 MHz spectrometer. Chemical shifts are reported in ppm (δ) downfield from tetramethylsilane (TMS) as an internal standard. Coupling constants (J) are given in Hz. Specific NMR assignments ( 1 H, 13 C) of synthesized and purified products 2-4 below, based on 2D NMR studies (COSY, HSQC, HMBC, NOESY), are available in Supporting Information. Accurate mass determination (HRMS) was performed on a "Synapt G2-S" Q-TOF instrument from Water TM. Samples were ionized with an ASAP probe (APCI) or ESI probe with no chromatographic separation performed prior to mass analysis. Calculated exact mass and spectra processing was done by Waters TM Software Masslynx V4.1 SCN871.